8个月推进至IND关键里程碑，药明康德如何助力客户突破双靶点小核酸偶联药物开发难题？| Bilingual

随着化学修饰与递送技术的日趋成熟，RNAi疗法正迎来从“单点精准靶向”向“多点协同调控”的升级。在这一创新浪潮中，二价双靶点siRNA（divalent dual-targeting siRNA）凭借独特的设计逻辑，展现出协同治疗潜力——用一个分子同时干预两个致病靶点，有望为复杂疾病的治疗带来新突破。尽管这一策略前景可期，但工艺开发和生产所面临的技术挑战，同样不容忽视。

攻克复杂寡核苷酸偶联药物的CMC瓶颈

一家客户带着一个二价双靶点siRNA-GalNAc偶联药物项目找到药明康德旗下的WuXi TIDES，目标明确而紧迫：8个月内完成从工艺开发到IND申报所需的全部CMC工作。

这是一种比传统单靶点siRNA更为复杂的寡核苷酸偶联分子类型。它采用三链结构，包含一条超过40个核苷酸的长正义链（其需要互补两条反义链），长度约为典型siRNA链的两倍，这意味着固相合成需要更多的步骤，累计收率将显著降低。该结构特征给合成、退火过程以及分析方法开发，都带来了更为复杂的技术挑战。

该项目揭示了一个行业共性难题：新分子疗法在释放更强治疗潜力的同时，其日益复杂的分子结构也对合成工艺、递送策略等提出了更高要求，使得研发和生产环节的挑战同步攀升。面对复杂分子的技术壁垒与紧迫的时间窗口，药明康德在寡核苷酸领域的多年深耕发挥了重要作用。早在2018年，依托在化学领域长期积累的赋能经验与技术能力，药明康德成立了专注于多肽、寡核苷酸及相关化学偶联药物的WuXi TIDES平台。如今，这一平台已在寡核苷酸-GalNAc偶联药物的开发和生产方面积累了丰富的经验和灵活的解决方案。

凭借深厚的技术与经验积淀，团队接到任务后迅速锁定影响工艺开发效率与产品质量的关键瓶颈，并行推进多个CMC难题的攻关。

在合成工艺开发环节，针对粗品纯度和收率偏低的问题，团队快速优化了负载GalNAc的固相载体（即合成树脂），筛选了不同的树脂来源，并改进了合成工艺条件，有效提高了长链合成效率。优化后，粗品纯度从40%提高至75%，最终收率翻倍。

与此同时，针对三链结构本身带来的退火控制难题，团队开发了受控退火策略并优化各条链的配比，从而增强了组装的稳健性并显著降低了错误组装产物的产生。

此外，分析团队同步开展工作，通过建立基于不同原理的变性和非变性分析方法，顺利解决了因各链序列高度相似所导致的杂质分离难题，满足了监管审查需求，从而为后续IND申报奠定了基础。

通过上述多维度并行攻关，WuXi TIDES团队仅用8个月，成功将这一复杂结构的siRNA–GalNAc项目高效推进至IND阶段，充分验证了团队在复杂寡核苷酸偶联药物领域的工艺开发与交付能力。

一体化平台加速客户复杂寡核苷酸偶联药物开发

上述关键工艺和分析挑战的逐一解决，为项目快速推进奠定了坚实的技术基础。然而，要在有限的周期内交付项目，还需要工艺开发、分析方法开发与生产放大等并行推进与高效协同。正是这种模式，使整体项目周期压缩至8个月。在这一过程中，药明康德一体化、端到端CRDMO平台所具备的系统整合能力与资源调配效率，得到了充分验证。

以原料药与制剂的无缝衔接为例——对于复杂的寡核苷酸偶联药物而言，原料药的工艺优化需要与处方研究、制剂开发及生产计划紧密配合。项目启动后，团队即并行推进GalNAc固相载体的工艺开发与生产，以及原料药的工艺开发，仅用两个月便生产出Demo批次原料药。随后，原料药团队在持续工艺优化的同时，无缝启动GLP批次生产；制剂团队利用少量的原料药便同步开展处方前研究与制剂开发，有效缩短了制剂工程批的生产周期。紧接着，制剂工程批生产与原料药GMP批次生产平行推进，为后续制剂临床批生产争取了宝贵时间。

在整个项目周期中，依托一体化CMC平台，分析团队的方法开发和验证工作贯穿全程，为IND申报材料的顺利交付提供全程支持。

在一体化平台模式下，各团队并非简单地同时开展工作，而是在项目全程建立紧密的协作机制，提前识别并规避研发过程中的潜在瓶颈，在坚守高质量标准的同时，提升效率。此外，合成工艺、分析方法、质量体系的一致性，从工艺放大到分析方法转移，都大大提高了成功率，减少在方法转移时出现的偏差和重复验证工作，有助于CMC资料的一致性与监管接受度。这一模式使得跨阶段、跨团队、跨基地所产生的摩擦及风险大幅降低，让项目更快、更稳地往前推进，最终助力客户顺利达成关键里程碑。

这一合作案例，生动诠释了药明康德CRDMO平台的运作模式与赋能价值。得益于此，同时使用WuXi TIDES原料药与制剂一体化服务的项目数量持续攀升，2025年这类管线数量已达到2023年的两倍多。

如今，复杂寡核苷酸偶联技术和精准递送策略正不断拓展精准治疗的边界。依托一体化、端到端CRDMO平台，药明康德将持续赋能合作伙伴推进前沿疗法研发，通过为更多寡核苷酸偶联药物提供高效、灵活和高质量的解决方案，最终助力更多创新疗法早日造福全球患者。

8 Months to IND: How WuXi AppTec Leveraged Integrated Expertise to Resolve Divalent siRNA–GalNAc Conjugate Development Challenges

WuXi AppTec helped a client reach a key development milestone by applying integrated expertise to advance a dual targeting, divalent siRNA–GalNAc conjugate from the preclinical candidate compound (PCC) to investigational new drug (IND) submission within 8 months. Rapid IND readiness was achieved not just by solving synthesis and analytical challenges, but by running process development, analytical development, and manufacturing in parallel rather than sequentially. That is the value of its platform—combining drug substance, drug product, analytical, and manufacturing to deliver an IND-ready CMC package on an accelerated timeline.

WuXi AppTec Overcomes CMC Challenges for Complex Oligonucleotide Conjugate Drug

The client developing the complex divalent dual-targeting siRNA–GalNAc conjugate approached WuXi TIDES, WuXi AppTec’s integrated CRDMO platform supporting drug discovery, development, and manufacturing for oligonucleotides, peptides, and related conjugated medicines. 

This was a more complex modality than a standard single-target siRNA. The molecule contained three strands, including a sense strand of more than 40 nucleotides (which anneal with two antisense strands), roughly twice the length of a typical siRNA strand which increased the number of solid phase coupling steps and substantially reduced yield, and posed significant challenges for synthesis, annealing, and analytical control.

This project reflects a common industry challenge: new therapeutic modalities offer greater potential, but their increasingly complex structures require more from synthesis and delivery, which adds to the difficulties in development and manufacturing. 

The WuXi TIDES team quickly identified the factors constraining process development efficiency and product quality and resolved several CMC challenges in parallel.

During synthesis process development, the team optimized the GalNAc‑loaded solid support (the synthesis resin), screened different resin sources, and refined the synthesis conditions to overcome low crude purity and yield. As a result, crude purity improved from 40% to 75% and final yield nearly doubled.

Meanwhile, the team developed a controlled annealing strategy and optimized strand stoichiometry to address the challenges posed by the three-strand structure, improving assembly robustness and reducing unwanted intermediates.

Because the strand sequences were highly similar, impurity separation was difficult under both denaturing and non-denaturing conditions. In parallel, the analytical team established orthogonal denaturing and native analytical methods that provided the resolution needed to support IND filing.

Through parallel multi‑dimensional process development efforts, the team advanced this complex siRNA–GalNAc conjugate to the IND stage within just 8 months, a milestone that unequivocally demonstrates the platform’s robust capabilities in process development and execution for complex oligonucleotide conjugates.

Seamless Coordination Enables Complex Oligonucleotide Conjugate Development

Delivering the project within 8 months required more than resolving molecule-level technical problems; it also required combining drug substance, drug product, analytical, and manufacturing to deliver an IND-ready CMC package. WuXi AppTec's integrated, end to end TIDES CRDMO platform was key to this effort.

Another key factor was seamless coordination between drug substance and drug product teams. Because active pharmaceutical ingredient (API), formulation, and analytical activities were closely aligned, the team was able to move efficiently from process optimization into good laboratory practice (GLP) and good manufacturing practice (GMP) manufacturing, and then into drug product engineering (ENG) and clinical trial material (CTM) production. Specifically, the process development and manufacturing of the GalNAc‑loaded solid support were carried out simultaneously with drug substance process development, producing a demo batch within 2 months. The drug substance team then continued process optimization and seamlessly initiated the GLP batch. Meanwhile, the drug product team advanced preformulation and formulation development concurrently using only minimal amounts of API, shortening the time for the drug product ENG batch. Thereafter, the drug product ENG batch and the drug substance GMP batch proceeded in parallel, freeing up time for the drug product CTM batch.

Method development, validation, and ongoing analytical support were carried out throughout the project lifecycle, leveraging the integrated CMC platform to support the delivery of the IND package.

The value of the integrated platform model was reflected in this collaboration. Rather than simply working in parallel, teams maintained coordination throughout the project, anticipated and addressed potential bottlenecks early, and upheld quality standards while driving efficiency. This approach increases success rates, minimizes deviations and repetitive re-validation. In short, cross-stage, cross-team, and cross-site frictions and risks are substantially reduced, enabling faster, more reliable project progression. 

This is not an isolated example. The number of molecules in the WuXi TIDES pipeline using both API and drug product services has grown steadily and even has more than doubled between 2023 and 2025. That trend reflects growing demand for integrated development support, especially for more complex modalities.

Complex oligonucleotide conjugate technologies and precision delivery approaches continue to expand the possibilities of precision medicine. WuXi AppTec supports partners in advancing novel therapies through efficient, flexible, and high quality solutions for oligonucleotide conjugates, ultimately making new treatments available to patients.

Key Takeaways:

1. WuXi TIDES, WuXi AppTec’s integrated CRDMO platform supporting drug discovery, development, and manufacturing for oligonucleotides, peptides, and related synthetic conjugates, advanced a complex dual‑targeting, divalent siRNA–GalNAc conjugate from PCC to IND in eight months through its integrated platform.

2. WuXi TIDES addressed CMC challenges across synthesis, annealing, and analytical control in parallel, enabling timely IND readiness for a complex dual‑targeting, divalent siRNA–GalNAc conjugate.

3. WuXi TIDES’s integrated platform enabled parallel execution across drug substance, drug product, analytical, and manufacturing functions, with cross‑functional coordination that shortened the overall timeline.

4. WuXi TIDES supports partners in advancing novel therapies through efficient, flexible, and high quality solutions for oligonucleotide conjugates, ultimately making new treatments available to patients.

参考资料：

[1] Jadhav V, Vaishnaw A, Fitzgerald K, et al. RNA interference in the era of nucleic acid therapeutics[J]. Nat Biotechnol, 2024(42):394–405. DOI:https://doi.org/10.1038/s41587-023-02105-y

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